Esomeprazole magnesium 1, the (S)-enantiomer of the proton pump inhibitor omeprazole, was developed by AstraZeneca as a second-generation of Prilosec®, and is currently marketed as Nexium®.

Esomeprazole is effective for the treatment of conditions such as stomach and duodenal ulcers, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. Its mode of action is as a proton pump inhibitor, thereby reducing gastric acid levels in the stomach, permitting the stomach and esophagus to heal.
Chemically known as (T-4)-Bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolato]magnesium (1), esomeprazole magnesium can be prepared through processes known in the art.
Sigrist-Nelson et al. (Eur. J. Biochem. 1987, 166, 453-459) prepared optically active benzimidazole sulfoxides, with structural similarities to omeprazole, using the procedure of Pitchen et al. (J. Am. Chem. Soc. 1984, 160, 8188-8193). While the enantiomeric excesses reported were lower than those achieved by Pitchen et al., later work (Zhao, S. H. et al. Tetrahedron 1987, 43, 5135-5144) demonstrated that changes to the reaction conditions could offer improved results.
For instance, U.S. Pat. No. 5,948,789 discloses a process that involves an asymmetric oxidation of sulfide 2 with an enantiomeric excess of 87%. The optical purity of sulfoxide 1a could be then improved via recrystallization of the sodium analog of 1. However, this process suffers from various deficiencies including low (less than 50% on average) chemical yield.

Another method to prepare optically pure sulfoxide 1 employs resolution of a racemic mixture of the sulfoxide. For instance, WO 95/32957 teaches a method to obtain optically pure sulfoxide 1a in neutral form by separation of a diastereomeric mixture by chromatography followed by removal of the derivatizing agent. This process involves multiple steps and is not practical for industrial scale.
WO 92/08716 discloses a process to prepare enantiomerically pure pantoprazole, a structurally similar antiulcer drug developed by BYK GmbH, and enantiomerically pure (+)-omeprazole, which could also be adapted for esomeprazole (1a). This process is similar to WO '957 in which different diastereomers of the sulfoxide derivatives are separated by re-crystallization. Again this process requires multiple steps resulting in a low yield.
U.S. Pat. No. 5,929,244 by Astra reveals a process for the purification of an enantiomerically enriched sulfoxide mixture by re-crystallization in various organic solvents. This process is easy to operate but requires several re-crystallizations to achieve the requisite enantiomeric purity for use as a pharmaceutical.
In WO 03/089408, Sun Pharmaceutical discloses a similar process to US '789 in which chiral methyl mandelate is used followed by formation of a chiral Ti(IV) complex. The process suffers the same drawbacks as before, for example, additional chemical operations and low (less than 50%) yield.
US 2004/077869 discloses a novel process to produce optically pure sulfoxide 1a in neutral form in which the racemic or enantiomerically enriched sulfoxide is resolved by formation of a Ti(IV) complex using a Ti(OiPr)4/diethyl D-tartrate/L-mandelic acid system. This multi-step process is relatively complex, laborious, and low yielding.
U.S. Pat. No. 5,039,806, by AB Hassle, discloses the racemic preparation of derivatives 3 by either acylation of the sulfoxide or acylation of the corresponding sulfide, followed by oxidation. However, when compared to the present process, the chemical yields are low.
Therefore, an object of the invention is to provide a facile and commercially viable process to produce esomeprazole (1a), and its pharmaceutically acceptable alkali and alkaline earth salts, which overcomes some of the disadvantages of the prior art by providing an increased yield and a process that avoids isolating the unstable esomeprazole as an intermediate.
Similarly, an object of the invention is to provide a facile and commercially viable process to produce omeprazole, and its pharmaceutically acceptable alkali and alkaline earth salts, which overcomes some of the disadvantages of the prior art by providing an increased yield and a process that avoids isolating the unstable omeprazole as an intermediate.
EP 0 005 129, by AB Hassle, discloses the preparation of omeprazole, and other related benzimidazoles, via oxidation of the corresponding sulfide with meta-chloroperbenzoic acid. This procedure results in the isolation of the free-base of omeprazole.
EP 0 124 495, by AB Hassle, discloses the preparation of various salts of omeprazole, including sodium and magnesium, however, the process utilizes the free-base of omeprazole, making it unattractive for use on an industrial scale.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and a more detailed description of the preferred embodiments contained herein.